Alan K. Mallams, Randall R. Rossman, Ronald J. Doll, Viyyoor M. Girijavallabhan, Ashit K. Ganguly, Joanne Petrin, Lynn Wang, Robert Patton, W. Robert Bishop, Donna M. Carr, Paul Kirschmeier, Joseph J. Catino, Matthew S. Bryant, Kwang-Jong Chen, Walter A. Korfmacher, Cymbelene Nardo, Shiyong Wang, Amin A. Nomeir, Chin-Chung Lin, Zujun Li, Jianping Chen, Suining Lee, Janet Dell, Philip Lipari, Michael Malkowski, Bodan Yaremko, Ivan King, and Ming Liu
The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine to explore the SAR of of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b...